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Non-viral precision T cell receptor replacement for personalized cell therapy – Nature.com

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Nature (2022)
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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.
The T cell receptor (TCR) provides the fine specificity of T cells to recognize mutations in cancer cells 1-3. We developed a clinical-grade approach based on CRISPR/Cas9 non-viral precision genome editing to simultaneously knock-out the two endogenous TCR genes, TCRα (TRAC) and TCRβ (TRBC), and insert in the TRAC locus the two chains of a neoantigen-specific TCR (neoTCR), isolated from the patient’s own circulating T cells using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with refractory solid cancers received up to three distinct neoTCR-transgenic cell products, each expressing a patient-specific neoTCR, in a cell dose-escalation, first-in-human phase 1 clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome, and one grade 3 encephalitis. All had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease, and the other 11 had disease progression as best response on therapy. NeoTCR-transgenic T cells were detected in tumour biopsies post-infusion at frequencies higher than the native TCRs pre-infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs recognizing mutational neoantigens, the simultaneous knock-out of the endogenous TCR and knock-in of the neoTCRs using single-step, non-viral precision genome editing, the manufacturing of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene edited neoTCR T cell products, and the ability of the transgenic T cells to traffic to the patients’ tumours.
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These authors contributed equally: Susan P. Foy, Kyle Jacoby, and Daniela A. Bota
These authors jointly supervised this work: Antoni Ribas, Arati V. Rao, and Stefanie J. Mandl
PACT Pharma, South San Francisco, CA, USA
Susan P. Foy, Kyle Jacoby, Theresa Hunter, Zheng Pan, Eric Stawiski, Yan Ma, William Lu, Songming Peng, Clifford L. Wang, Benjamin Yuen, Olivier Dalmas, Katharine Heeringa, Barbara Sennino, Andy Conroy, Michael T. Bethune, Ines Mende, William White, Monica Kukreja, Swetha Gunturu, Emily Humphrey, Adeel Hussaini, Duo An, Adam J. Litterman, Boi Bryant Quach, Chad Smith, Daniel Anaya, Lindsey Skrdlant, Eva Yi-Hsuan Huang, Ventura Mendoza, Jyoti Mathur, Luke Dengler, Bhamini Purandare, Robert Moot, Michael C. Yi, Roel Funke, Alison Sibley, Todd Stallings-Schmitt, Alex Franzusoff, Arati V. Rao & Stefanie J. Mandl
Department of Neurology and Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, USA
Daniela A. Bota
Institute for Systems Biology, Seattle, WA, USA
Alphonsus H. C. Ng, Yue Lu & James R. Heath
Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA
Katie M. Campbell, Bartosz Chmielowski & Antoni Ribas
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA
David Y. Oh
Jonsson Comprehensive Cancer Center at the University of California Los Angeles, Los Angeles, CA, USA
Bartosz Chmielowski & Antoni Ribas
Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
Mehrdad Abedi
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
Yuan Yuan
Department of Medicine and Robert H. Lurie Cancer Center, Northwestern University, Evanston, IL, USA
Jeffrey A. Sosman
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Sylvia M. Lee
Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
Adam J. Schoenfeld
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
David Baltimore
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Correspondence to Susan P. Foy, Antoni Ribas or Stefanie J. Mandl.
This Supplementary Information file includes: Supplemental Figures 1–8, Supplemental Tables 1 and 3, and Clinical Trial Protocol.
Full length TCR sequences.
List of flow cytometry reagents.
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Foy, S.P., Jacoby, K., Bota, D.A. et al. Non-viral precision T cell receptor replacement for personalized cell therapy. Nature (2022). https://doi.org/10.1038/s41586-022-05531-1
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DOI: https://doi.org/10.1038/s41586-022-05531-1
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